Blood-brain barrier opening with focused ultrasound reduces neuromelanin in a non-human primate model.

Authors

Noelia Esteban-García, Carolina Martín-Flórez, José A Pineda-Pardo, Miguel López-Aguirre, Megan Carrillo, Rafael Rodríguez-Rojas, Inés Trigo-Damas, José L Lanciego, Miquel Vila, José A Obeso, Javier Blesa

Published in

Brain : a journal of neurology. Oct 05, 2026. Epub Oct 05, 2026.

Abstract

Age-related accumulation of neuromelanin (NM) has been implicated in the intrinsic vulnerability of catecholaminergic neurons in Parkinson's disease. Postmortem studies in Parkinson's disease patients have revealed elevated intracellular and extracellular NM in the substantia nigra pars compacta, whereas experimental enhancement of NM synthesis in animal models disrupts neuronal homeostasis and accelerates neurodegeneration. Low-intensity focused ultrasound combined with microbubbles (LIFU-MB) induces focal opening of the blood-brain barrier. It has been shown to influence protein aggregation and modulate pigment-related processes, thereby raising the possibility that it may also impact NM dynamics in the brain. Here, we investigated the possibility that repeated LIFU-MB-mediated blood-brain barrier opening could modify NM accumulation in a non-human primate model that overexpresses human tyrosinase, leading to elevated NM accumulation in the substantia nigra pars compacta. Comprehensive characterization revealed that these animals exhibit several features compatible with early pathological changes in Parkinson's disease including extracellular NM release, increased iron accumulation, nigral inflammatory changes, and intracellular inclusion formation. Importantly, these alterations occur in the absence of substantial dopaminergic cell loss and behavioral deficits. LIFU-MB-treated animals showed a marked reduction in both intracellular and extracellular NM, accompanied by a trend toward decreased free ferric iron. These results indicate that early, non-invasive LIFU-MB intervention can counteract mechanisms linked to excessive NM accumulation. Moreover, this approach provides a translational framework to explore the broader feasibility of reducing intracellular pigments and pathological aggregates in the brain. Given its clinical safety, capacity to reach deep brain structures, and non-invasive nature, LIFU-MB warrants further investigation as a possible therapeutic approach in Parkinson´s disease and other neurodegenerative disorders.

PMID:
42831534
Bibliographic data and abstract were imported from PubMed on 05 Oct 2026.

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